RESUMO
Heterozygous fumarate hydratase (FH) germline mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer. The main objective of our study was to evaluate clinical and genetic data from families suspected of HLRCC on a nationwide level. All families referred for FH mutation analysis in the Netherlands were assessed. We performed FH sequence analysis and multiplex ligation-dependent probe amplification. Families with similar FH mutations were examined for haplotype sharing. In 14 out of 33 families, we identified 11 different pathogenic FH germline mutations, including 4 novel mutations and 1 whole-gene deletion. Clinical data were available for 35 FH mutation carriers. Cutaneous leiomyomas were present in all FH mutation carriers older than 40 years of age. Eleven out of 21 female FH mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas at an average of 35 years. Two FH mutation carriers had papillary type 2 renal cancer and Wilms' tumour, respectively. We evaluated the relevance of our findings for clinical practice and have proposed clinical diagnostic criteria, indications for FH mutation analysis and recommendations for management.
Assuntos
Carcinoma de Células Renais/genética , Fumarato Hidratase , Mutação em Linhagem Germinativa , Neoplasias Renais/genética , Leiomiomatose , Neoplasias Cutâneas/genética , Neoplasias Uterinas/genética , Adolescente , Adulto , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/enzimologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Fumarato Hidratase/genética , Predisposição Genética para Doença , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/enzimologia , Leiomiomatose/enzimologia , Leiomiomatose/genética , Países Baixos , Linhagem , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/enzimologia , Síndrome , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/enzimologia , Adulto JovemAssuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Leiomiomatose/genética , Síndromes Neoplásicas Hereditárias/genética , Tumor de Wilms/genética , Adulto , Análise Mutacional de DNA/métodos , Feminino , Fumarato Hidratase/genética , Humanos , Mutação de Sentido Incorreto , LinhagemRESUMO
NOD2/CARD15 belongs to the N-terminal caspase recruitment domain family of proteins involved in regulating NF-kB activation in response to inflammatory stimuli transduced through Toll-like receptors. Mutations and polymorphisms in the NOD2/CARD15 gene reduce antibacterial responses and are associated with granulomatous inflammatory conditions such as Blau syndrome and early-onset sarcoidosis. The polymorphism R702W (arginine to tryptophan) is strongly associated with susceptibility to Crohn's disease in Caucasian populations. Skin abnormalities (other than cutaneous manifestations of Crohn's disease) have not been previously associated with R702W. We report on a female patient homozygous for R702W who developed granulomatous rosacea at the age of 12 years old. From the occurrence in the context of Crohn associated with R702W, we speculate that granulomatous rosacea may be an entity distinct from other forms of rosacea, which are associated with increased production of antibacterial proteins such as cathelicidin.
Assuntos
Doença de Crohn/genética , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo Único , Rosácea/genética , Criança , Doença de Crohn/complicações , Feminino , Homozigoto , Humanos , Mutação de Sentido Incorreto , Rosácea/complicaçõesAssuntos
Ictiose/genética , Lipase/metabolismo , Erros Inatos do Metabolismo Lipídico/genética , Doenças Musculares/genética , Mutação/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferase , Criança , Consanguinidade , Diagnóstico Diferencial , Hepatomegalia/diagnóstico , Humanos , Lipase/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Masculino , Fenótipo , SíndromeRESUMO
Multiple cutaneous and uterine leiomyomatosis (MCUL; OMIM 150800) is an autosomal dominantly inherited disease characterized by leiomyomas of the skin and uterine leiomyomas. MCUL can be associated with various types of renal cancer. This syndrome is known as hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839). Both disorders result from heterozygous germline mutations in the fumarate hydratase (FH) gene.
